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An intriguing challenge of drug discovery is targeting pathogenic mutant proteins that differ from their wild-type counterparts by only a single amino acid. In particular, pathogenic cysteine mutations afford promising opportunities for mutant-specific drug discovery, due to the unique reactivity of cysteine's sulfhydryl-containing side chain. Here we describe the first directed discovery effort targeting a pathogenic cysteine mutant of a protein tyrosine phosphatase (PTP), namely Y279C Src-homology-2-containing PTP 2 (SHP2), which has be